Clinicopathological Features and Molecular Signatures of Lateral Neck Lymph Node Metastasis in Papillary Thyroid Microcarcinoma.

BACKGRUOUND: The predictive factors for lateral neck lymph node metastasis (LLNM) in papillary thyroid microcarcinoma (PTMC) remain undetermined. This study investigated the clinicopathological characteristics, transcriptomes, and tumor microenvironment in PTMC according to the LLNM status. We aimed to identify the biomarkers associated with LLNM development. METHODS: We retrospectively reviewed the medical records of patients with PTMC from two independent institutions between 2018 and 2022 (n=597 and n=467). We compared clinicopathological features between patients without lymph node metastasis (N0) and those with LLNM (N1b). Additionally, laser capture microdissection and RNA sequencing were performed on primary tumors from both groups, including metastatic lymph nodes from the N1b group (n=30; 20 primary tumors and 10 paired LLNMs). We corroborated the findings using RNA sequencing data from 16 BRAF-like PTMCs from The Cancer Genome Atlas. Transcriptomic analyses were validated by immunohistochemical staining. RESULTS: Clinicopathological characteristics, such as male sex, multifocality, extrathyroidal extension, lymphatic invasion, and central node metastasis showed associations with LLNM in PTMCs. Transcriptomic profiles between the N0 and N1b PTMC groups were similar. However, tumor microenvironment deconvolution from RNA sequencing and immunohistochemistry revealed an increased abundance of tumor-associated macrophages, particularly M2 macrophages, in the N1b group. CONCLUSION: Patients with PTMC who have a male sex, multifocality, extrathyroidal extension, lymphatic invasion, and central node metastasis exhibited an elevated risk for LLNM. Furthermore, infiltration of M2 macrophages in the tumor microenvironment potentially supports tumor progression and LLNM in PTMCs.

miR-22-3p and miR-30e-5p Are Associated with Prognosis in Cervical Squamous Cell Carcinoma.

Alteration in expression of miRNAs can cause various malignant changes and the metastatic process. Our aim was to identify the miRNAs involved in cervical squamous cell carcinoma (SqCC) and metastasis, and to test their utility as indicators of metastasis and survival. Using microarray technology, we performed miRNA expression profiling on primary cervical SqCC tissue (n = 6) compared with normal control (NC) tissue and compared SqCC that had (SqC-M; n = 3) and had not (SqC-NM; n = 3) metastasized. Four miRNAs were selected for validation by qRT-PCR on 29 SqC-NM and 27 SqC-M samples, and nine metastatic lesions (ML-SqC), from a total of 56 patients. Correlation of miRNA expression and clinicopathological parameters was analyzed to evaluate the clinical impact of candidate miRNAs. We found 40 miRNAs differentially altered in cervical SqCC tissue: 21 miRNAs were upregulated and 19 were downregulated (≥2-fold, p < 0.05). Eight were differentially altered in SqC-M compared with SqC-NM samples: four were upregulated (miR-494, miR-92a-3p, miR-205-5p, and miR-221-3p), and four were downregulated (miR-574-3p, miR-4769-3p, miR-1281, and miR-1825) (≥1.5-fold, p < 0.05). MiR-22-3p might be a metastamiR, which was gradually further downregulated in SqC-NM > SqC-M > ML-SqC. Downregulation of miR-30e-5p significantly correlated with high stage, lymph node metastasis, and low survival rate, suggesting an independent poor prognostic factor.

Low Expression of EphB2, EphB3, and EphB4 in Bladder Cancer: Novel Potential Indicators of Muscular Invasion.

PURPOSE: Eph receptors are differentially expressed in numerous malignant tumors. This study intended to analyze the roles of EphB receptors (EphB2, B3, and B4) in urinary bladder cancer. MATERIALS AND METHODS: Tissue microarray-based immunohistochemical analysis was used to investigate the expression patterns of EphB2, EphB3, and EphB4 in 154 bladder cancer specimens. Immunohistochemical staining was conducted examining the extent of stained cells and staining intensity. EphB was considered to be highly expressed when the intensity of staining was more than moderate in >25% of cells in the tissue section. Small interfering RNA (siRNA) was used to knock down EphB expression in bladder cancer cell lines (T24, 5637) to determine the effects of EphB on tumor cell invasion, proliferation, and migration. RESULTS: EphB receptors (B2, B3, and B4) were detected in 40.9% (EphB2, 63/154), 71.4% (EphB3, 110/154), and 53.2% (EphB4, 82/154) of bladder cancer specimens. Low expression of EphB2, B3, and B4 receptors were significantly associated with higher tumor grade (EphB2, p<0.001; EphB3, p=0.032; EphB4, p<0.001) and muscular invasion (EphB2, p=0.002; EphB3, p=0.009; EphB4, p<0.001). No obvious correlation was observed with other clinicopathological variables, such as age, sex, recurrence, lymph node involvement, metastasis, and overall survival. Inactivation of EphB receptors by siRNA transfection increased cell viability, tumor cell invasion, proliferation, and migration in comparison with untransfected cancer cells. CONCLUSION: Low expression of EphB receptors (B2, B3, and B4) can be a predictive marker for muscular invasion of bladder cancer.

MicroRNA signatures associated with lymph node metastasis in intramucosal gastric cancer.

Although a certain proportion of intramucosal carcinomas (IMCs) of the stomach does metastasize, the majority of patients are currently treated with endoscopic resection without lymph node dissection, and this potentially veils any existing metastasis and may put some patients in danger. In this regard, biological markers from the resected IMC that can predict metastasis are warranted. Here, we discovered unique miRNA expression profiles that consist of 21 distinct miRNAs that are specifically upregulated (miR-628-5p, miR-1587, miR-3175, miR-3620-5p, miR-4459, miR-4505, miR-4507, miR-4720-5p, miR-4742-5p, and miR-6779-5p) or downregulated (miR-106b-3p, miR-125a-5p, miR-151b, miR-181d-5p, miR-486-5p, miR-500a-3p, miR-502-3p, miR-1231, miR-3609, and miR-6831-5p) in metastatic (M)-IMC compared to nonmetastatic (N)-IMC, or nonneoplastic gastric mucosa. Intriguingly, most of these selected miRNAs showed stepwise increased or decreased expression from nonneoplastic tissue to N-IMC to M-IMC. This suggests that common oncogenic mechanisms are gradually intensified during the metastatic process. Using a machine-learning algorithm, we demonstrated that such miRNA signatures could distinguish M-IMC from N-IMC. Gene ontology and pathway analysis revealed that TGF-ß signaling was enriched from upregulated miRNAs, whereas E2F targets, apoptosis-related, hypoxia-related, and PI3K/AKT/mTOR signaling pathways, were enriched from downregulated miRNAs. Immunohistochemical staining of samples from multiple institutions indicated that PI3K/AKT/mTOR pathway components, MAPK1, phospho-p44/42 MAPK, and pS6 were highly expressed and the expression of SMAD7, a TGF-ß pathway component, was decreased in M-IMC, which could aid in distinguishing M-IMC from N-IMC. The miRNA signature discovered in this study is a valuable biological marker for identifying metastatic potential of IMCs, and provides novel insights regarding the metastatic progression of IMC.

Empagliflozin attenuates diabetic tubulopathy by improving mitochondrial fragmentation and autophagy.

We examined the effects of empagliflozin, a selective inhibitor of Na+-glucose cotransporter 2, on mitochondrial quality control and autophagy in renal tubular cells in a diabetic environment in vivo and in vitro. Human renal proximal tubular cells (hRPTCs) were incubated under high-glucose conditions. Diabetes was induced with streptozotocin in male C57BL/6J mice. Improvements in mitochondrial biogenesis and balanced fusion-fission protein expression were noted in hRPTCs after treatment with empagliflozin in high-glucose media. Empagliflozin also increased autophagic activities in renal tubular cells in the high-glucose environment, which was accompanied with mammalian target of rapamycin inhibition. Moreover, reduced mitochondrial reactive oxygen species production and decreased apoptotic and fibrotic protein expression were observed in hRPTCs after treatment with empagliflozin, even in the hyperglycemic circumstance. Importantly, empagliflozin restored AMP-activated protein kinase-α phosphorylation and normalized levels of AMP-to-ATP ratios in hRPTCs subjected to a high-glucose environment, which suggests the way that empagliflozin is involved in mitochondrial quality control. Empagliflozin effectively suppressed Na+-glucose cotransporter 2 expression and ameliorated renal morphological changes in the kidneys of streptozotocin-induced diabetic mice. Electron microscopy analysis showed that mitochondrial fragmentation was decreased and 8-hydroxy-2'-deoxyguanosine content was low in renal tubular cells of empagliflozin treatment groups compared with those of the diabetic control group. We suggest one mechanism related to the renoprotective actions of empagliflozin, which reverse mitochondrial dynamics and autophagy.

A novel PI3K/mTOR dual inhibitor, CMG002, overcomes the chemoresistance in ovarian cancer.

OBJECTIVE: Ovarian cancer is the leading cause of gynecologic-related mortality worldwide. Despite successful initial treatment, overall survival rates are very low because tumors develop resistance to chemotherapeutic drugs. The PI3K/mTOR pathway is a key signaling pathway involved in drug resistance of ovarian cancer cells. The aim of this study was to examine the effect of a newly developed PI3K/mTOR dual inhibitor, CMG002, on chemoresistant ovarian cancer cells. METHODS: We examined the effects of CMG002, and its synergistic effects when combined with paclitaxel or cisplatin, on cell viability, cell cycle arrest, and apoptosis of PTX-resistant SKpac17 or cisplatin-resistant A2780cis ovarian cancer cells in vitro. Western blot analysis was performed to assess expression of PI3K, p-mTOR, p-Akt, p-S6, Bim, and caspase-3. In vivo studies were carried out in a xenograft mouse model, followed by TUNEL and immunohistochemical staining of excised tumor tissue. RESULTS: CMG002 showed marked toxicity against chemoresistant ovarian cancer cells and re-sensitized these cells to chemotherapeutic agents by suppressing cell proliferation and inducing G1 cell cycle arrest and apoptosis. In vivo xenograft studies revealed that treatment with CMG002, either alone or in combination with paclitaxel or cisplatin, led to a marked reduction in tumor growth. CMG002 caused marked suppression of mTOR (Ser2448), Akt (Ser473), Akt (Thr308), and S6 (Ser235/236) phosphorylation, both in vitro and in vivo. CONCLUSION: Taken together, CMG002, a very potent PI3K/mTOR dual inhibitor, induced cytotoxicity in chemoresistant ovarian cancer cells, suggesting that this novel inhibitor might be a new therapeutic strategy for chemoresistant ovarian cancer.

Minimal deviation adenocarcinoma (adenoma malignum) of the uterine cervix: clinicopathological analysis of 17 cases.

OBJECTIVE: The aim of this study was to evaluate the clinicopathological features of minimal deviation adenocarcinoma (MDA) and to analyze its prognostic factors. METHODS: We retrospectively analyzed the medical records of 17 patients who were diagnosed with MDA at a single institution between January 2005 and December 2015. RESULTS: The median age of the patients was 47.7 years (33-75 years). MDA was diagnosed in 7 patients (41.2%) before performing definitive surgery. Stage IB disease was diagnosed in 12 patients (70.6%) and advanced stage disease (stage II: 3, stage III: 2) in 5. MDA was incidentally diagnosed following hysterectomy for benign conditions in 6 patients. Adjuvant therapy was administered to 13 patients (76.5%). During median follow-up over 33.6 months (7-99 months), 11 patients (64.7%) showed no evidence of disease, 6 (35.3%) showed persistent or recurrent disease and 5 died of the disease. Peutz-Jeghers syndrome was not suspected in any patient, and no mutation was detected in the 3 patients who underwent genetic testing. Univariate analysis showed that advanced stage disease (P=0.016) and lymphovascular space invasion (P=0.002) demonstrated a statistically significant association with poor overall survival (OS) rates. Advanced stage disease continued to show a significant association with poor OS rates (hazard ratio, 2.92; 95% confidence interval, 1.097-7.746; P=0.032) even after multivariate analysis. CONCLUSION: Early diagnosis is important to manage MDA. Clinicians should consider MDA among the differential diagnoses in patients with a suspicious clinical presentation even with negative cervical screening tests.

A clinicopathologic review and obstetric outcome of uterine smooth muscle tumor of uncertain malignant potential (STUMP) in a single institution.

OBJECTIVES: The present study aimed to analyze the clinicopathologic features and treatment of uSTUMP in a single institution. In addition, we described the obstetric outcomes after uterine-preserving surgery for uSTUMP. METHODS AND MATERIALS: A retrospective chart review was performed of patients diagnosed with uSTUMP between January 2000 and February 2018 at the Comprehensive Gynecologic Cancer Center, CHA Bundang Medical Center. We obtained data on the patients' demographics, treatment, therapeutic results, time to recurrence, disease-free and overall survival, and subsequent obstetric outcomes. The central pathology reviews were carried out by two pathologists specializing in gynecologic oncology. RESULT: A total of 19 patients diagnosed with uSTUMP were identified and included in the study. The mean age at diagnosis was 41 years (range 28-49 years). Frozen sections were performed in 11 patients including five patients during surgery. Nine of the 19 patients (47.4%) were treated by hysterectomy and 10 patients were initially treated by myomectomy. The mean follow-up period was 47 months (range 6-209 months). Two patients (10.5%; 2/19) experienced recurrence. Although not defined as recurrence in the present study criteria, one patient had a secondary diagnosis of atypical leiomyoma one year after the initial diagnosis of uSTUMP. Seven patients requested uterine-preserving treatment, five of whom wanted to become pregnant. Three of them (3/5; 60%) successfully delivered live birth to full term by Cesarean section without complications such as abortion, preterm delivery or uterine rupture, and tumor recurrence. CONCLUSIONS: The present study describes the clinicopathologic data of uSTUMP patients. Our results suggest a uSTUMP recurrence of 10.5%, comparable to previous reports. Although there is a possibility of malignant recurrence, fertility-preserving management is worth attempting because of relatively low affected age with careful close follow-up.

Chloroquine and amodiaquine enhance AMPK phosphorylation and improve mitochondrial fragmentation in diabetic tubulopathy.

We investigated the effects of chloroquine (CQ) and amodiaquine (AQ) on AMPK phosphorylation in renal tubular cells in a diabetic environment in vivo and in vitro. We also examined whether CQ- or AQ-mediated AMPK activity restoration attenuated diabetic tubulopathy by normalizing mitochondrial fragmentation. Human renal proximal epithelial cells (HKC8) were incubated in high-glucose conditions. Diabetes was induced with streptozotocin in male C57/BL6J mice. Treatment with CQ or AQ abolished high-glucose-induced phospho-AMPK and phosph-PGC1α down-regulation in HKC8 cells. Improvements in functional mitochondrial mass and balanced fusion/fission protein expression were observed in HKC8 cells after treatment with CQ or AQ in high-glucose conditions. Moreover, decreased mitochondrial ROS production and reduced apoptotic and fibrotic protein expression were noted in HKC8 cells after treatment with CQ or AQ, even in high-glucose conditions. CQ and AQ treatment effectively mitigated albuminuria and renal histopathologic changes and increased AMPK activity in the kidneys of diabetic mice. Electron microscopy analysis showed that mitochondrial fragmentation was decreased, and 8-OHdG content was low in the renal tubular cells of the CQ and AQ treatment groups compared with those of the diabetic control group. Our results suggest that CQ and AQ may be useful treatments for patients with diabetic kidney disease.

Fascin expression is inversely correlated with breast cancer metastasis suppressor 1 and predicts a worse survival outcome in node-negative breast cancer patients.

Background: Fascin is an actin-bundling protein that promotes cancer cell migration and invasion. By contrast, breast cancer metastasis suppressor 1 (BRMS1) inhibits cancer metastasis by targeting multiple steps of the metastatic cascade. We evaluated whether expression patterns of fascin and BRMS1 correlate with clinicopathological features and patient outcome. Methods: Immunohistochemistry for fascin and BRMS1 was performed using a tissue microarray constructed from 183 human breast cancer tissues. Fascin expression determined by the proportion of stained tumor cells (0: 0-5%, 1: 6-25%, 2: 26-50%, 3: 51-75%, or 4: >75%) and staining intensity (0: negative, 1: weak, 2: moderate, or 3: strong) were multiplied and defined as negative (0-3) or positive (4-12). BRMS1 expression was scored separately based on nuclear and cytoplasmic staining intensity (0: negative, 1: weak, 2: moderate, 3: strong). We obtained the BRMS1 H score by summing the nuclear and cytoplasmic scores and defined it as negative (0-2) or positive (3-6). Results: Expression of BRMS1 showed a significant inverse correlation with that of fascin. Fascin+ tumors were significantly associated with no lymph node metastasis, higher histological and higher nuclear grade, ER/PR/HER2 negativity, and triple-negative subtype (all ps < 0.05). These clinicopathological differences showed the same trend in a comparison of fascin-/BRMS1+ and fascin+/BRMS1- tumors. Negative or weak BRMS1 cytoplasmic expression was significantly associated with shorter disease-free survival (DFS; p = 0.043). Fascin positivity was significantly associated with shorter DFS (p = 0.005) and overall survival (p = 0.020) when analyses were confined to node-negative patients. Conclusions: This study confirms an inverse correlation between expression of fascin and expression of BRMS1 using a quite large cohort of human breast cancer tissues. Fascin alone or combined with BRMS1 was a worse prognostic marker, particularly in node-negative breast cancer patients.

miR-150 enhances apoptotic and anti-tumor effects of paclitaxel in paclitaxel-resistant ovarian cancer cells by targeting Notch3.

Tumor recurrence by obtaining chemoresistance is a major obstacle to treating ovarian cancer. By TargetScan database and a luciferase reporter assay, we identified miR-150 directly targets Notch3, which is a key oncogene in ovarian cancer. We, therefore, investigated the role of miR-150 in ovarian cancer cells, and the usefulness of miR-150 as a therapeutic target in chemoresistant ovarian cancer, through examining miR-150 expression by qRT-PCR in ovarian cancer cell lines and tissues, and assessing the gain-of-function effect by WST, colony forming, TUNEL, wound healing and angiogenesis assays. Western blotting was performed to evaluate its downstream targets. The miR-150 expression was significantly downregulated in ovarian cancers. Treatment with pre-miR-150 significantly inhibited cancer cell proliferation, and induced apoptosis in PTX (paclitaxel) -resistant SKpac cells, which was not seen by PTX only treatment. On spheroid forming assay, an additional pre-miR-150 treatment with PTX decreased cancer stem cell activation in PTX-resistant SKpac cells. An experimental upregulation of miR-150 also decreased cancer cell migration and angiogenesis in SKpac cells. The Notch3 downstream proteins(NICD3 and HEY2), and cell cycle-related proteins (cyclinD3, pS6, and NF-kB), and apoptosis-related proteins (BCL-2 and BCL-W) were significantly downregulated by pre-miR-150 transfection. Taken together, miR-150 is related with PTX-resistance in ovarian cancer, and treatment with pre-miR-150 resensitizes cancer cells to PTX. Therefore, it may be a promising treatment strategy in chemoresistant and recurrent ovarian cancer.

MicroRNA-136 inhibits cancer stem cell activity and enhances the anti-tumor effect of paclitaxel against chemoresistant ovarian cancer cells by targeting Notch3.

To identify microRNAs (miRNAs) regulating Notch3 expression in association with paclitaxel resistance, candidate miRNAs targeting Notch3 were predicted using TargetScan. We found that miR-136 directly targets Notch3, and miR-136 was significantly downregulated in OSC tissues relative to normal control tissues, and low expression of miR-136 correlated with poor overall in ovarian cancer patients. Artificial miR-136 overexpression significantly reduced cell viability, proliferation, Cancer stem cell (CSC) spheroid formation, and angiogenesis, and increased apoptosis in paclitaxel-resistant SKpac cells compared with the effects of paclitaxel alone. miR-136 overexpression downregulated cell survival- (survivin, DNA-PK, pS6, S6) and cell cycle- (Cyclin D1, NF-κB) related proteins, and anti-apoptotic proteins (BCL2, and BCL-XL), and upregulated pro-apoptotic proteins (Bim, Bid, and Bax). Taken together, miR-136 targets the Notch3 oncogene and functions as a tumor suppressor. miR-136 overexpression resensitized paclitaxel-resistant ovarian cancer cells and reduced CSC activities, suggesting a promising new target for the treatment of chemoresistant ovarian cancers.

Sox10 expression in ovarian epithelial tumors is associated with poor overall survival.

Sox10 is a transcription factor regulating the development of several cell lineages and is involved in tumor development. However, the clinicopathological relevance of Sox10 expression in ovarian cancer has not been examined. We assessed expression of Sox10 in ovarian epithelial tumors by immunohistochemistry and assessed its prognostic value by analyzing the correlation between its expression and clinicopathological factors. We used tissue microarrays including 244 ovarian epithelial tumors. Sox10 staining was found in the cytoplasm or nucleus of tumor cells. Malignant serous, mucinous, and endometrioid tumors were significantly more likely to express Sox10 than benign and borderline tumors. Expression patterns in adenocarcinomas were different for histologic subtypes: nuclear Sox10 staining was common in clear-cell adenocarcinomas and serous adenocarcinomas, whereas all cases of mucinous and endometrioid tumors were negative for nuclear staining. Nuclear Sox10 staining was also associated with chemoresistance and shorter overall survival in ovarian adenocarcinomas, notably in high-grade serous adenocarcinoma. Sox10 is expressed in many ovarian carcinomas, suggesting that it might be involved in oncogenesis of ovarian carcinoma. Expression pattern of Sox10 differs between histological subtypes. Nuclear Sox10 expression is an independent indicator of poor prognosis in ovarian adenocarcinomas, notably in high-grade serous adenocarcinomas.

Spermatic Cord Paraganglioma With Histologically Malignant Features.

Paragangliomas occur extremely rarely in the spermatic cord. A 40-year-old man presented with a scrotal mass that was diagnosed as spermatic cord paraganglioma with malignant histological features. To our knowledge, this is the first case of spermatic cord paraganglioma presented with malignant histological features evaluated by histological scoring. Careful evaluation of histological features and systematic evaluation should be considered for patients with spermatic cord paragangliomas.

Fibulin-5 is a tumour suppressor inhibiting cell migration and invasion in ovarian cancer.

AIMS: Fibulin-5 is an extracellular matrix (ECM) glycoprotein which has a role in the organisation and stabilisation of ECM structures and regulating cell proliferation and tumourigenesis. Here, the expression of fibulin-5 and its functional effects on the migration and invasion of ovarian cancer cells were assessed. METHODS: Expression of fibulin-5 was detected in 44 ovarian tumour tissues by qRT-PCR, Western blotting and immunohistochemistry. We performed cell migration and invasion assays, and cell cycle analysis in fibulin-5 transfected SKOV3 (SKOV3-FBLN5) cells and the parental SKOV3 cells. We further examined the expression of three tissue inhibitors of metalloproteinases (TIMPs) and seven matrix metalloproteinases (MMPs) by RT-PCR. RESULTS: mRNA and protein expression of fibulin-5 were down-regulated (0.05-fold and 0.1-fold) in ovarian carcinomas compared with control tissues (p<0.01 and p=0.022). In wound-healing and invasion assays, significantly fewer SKOV3-FBLN5 cells than SKOV3 control cells migrated and invaded (39.1%, p=0.046 and 70%, p=0.03, respectively), which was reversed by siRNA-treatment. Overexpression of fibulin-5 induced G2/M arrest and increased cyclin B1, CDC2 and CDC25C. Expression of TIMP-2 (0.56-fold), MMP-3 (0.43-fold) and MMP-13 (0.18-fold) was lower and MMP-9 expression (2.20-fold) was higher in SKOV3-FBLN5 cells than in control cells. CONCLUSIONS: Fibulin-5 is significantly down-regulated in ovarian carcinoma and acts as a tumour suppressor by inhibiting the migration and invasion of ovarian cancer cells.

Germline Mutations of BRCA1 and BRCA2 in Korean Ovarian Cancer Patients: Finding Founder Mutations.

OBJECTIVES: To investigate and analyze the BRCA mutations in Korean ovarian cancer patients with or without family history and to find founder mutations in this group. METHODS/MATERIALS: One hundred two patients who underwent a staging operation for pathologically proven epithelial cancer between January 2013 and December 2014 were enrolled. Thirty-two patients declined to analyze BRCA1/2 gene alterations after genetic counseling and pedigree analysis. Lymphocyte specimens from peripheral blood were assessed for BRCA1/2 by direct sequencing. RESULTS: BRCA genetic test results of 70 patients were available. Eighteen BRCA1/2 mutations and 17 unclassified variations (UVs) were found. Five of the BRCA1/2 mutations and 4 of the UVs were not reported in the Breast Cancer Information Core database. One BRCA2 UV (8665_8667delGGA) was strongly suspicious to be a deleterious mutation. BRCA1/2 mutations were identified in 11 (61.1%) of 18 patients with a family history and in 7 (13.5%) of 52 patients without a family history.Candidates for founder mutations in Korean ovarian cancer patients were assessed among 39 BRCA1/2 mutations from the present study and from literature reviews. The analysis showed that 1041_1043delAGCinsT (n = 4; 10.2%) and 3746insA (n = 4; 10.2%) were possible BRCA1 founder mutations. Only one of the BRCA2 mutations (5804_5807delTTAA) was repeated twice (n = 2; 5.1%). CONCLUSIONS: The prevalence of BRCA1/2 mutations in Korean ovarian cancer patients irrespective of the family history was significantly higher than previously reported. Possible founder mutations in Korean ovarian cancer patients were identified.

VAV3 Overexpressed in Cancer Stem Cells Is a Poor Prognostic Indicator in Ovarian Cancer Patients.

Ovarian carcinoma is a highly lethal malignancy due to frequent relapse and drug resistance. Cancer stem cells (CSCs) are thought to contribute significantly to disease relapse and drug resistance. In this study, a subpopulation of CSCs of ovarian carcinoma was isolated and the genes differentially expressed in these cells were identified to characterize CSCs and to find candidate biomarkers. Ovarian carcinoma cells from patients were primarily cultured, and spheroid-forming cells (SFCs) were isolated. The characteristic genes of SFCs were identified through cDNA microarray and validation by quantitative real-time polymerase chain reaction and immunohistochemistry, and the association of their expression with clinicopathologic parameters was analyzed. GSC (4.26-fold), VAV3 (7.05-fold), FOXA2 (12.06-fold), LEF1 (17.26-fold), COMP (21.33-fold), GRIN2A (9.36-fold), CD86 (23.14-fold), PYY (4.18-fold), NKX3-2 (10.35-fold), and PDK4 (74.26-fold) were significantly upregulated in SFCs compared with parental cancer cells. With validation for human ovarian carcinomas, LEF1, PYY, NKX3-2, and WNT3A were significantly upregulated in chemoresistant cancers compared with chemosensitive cancers. Overexpression of LEF1, VAV3, and NKX3-2 was significantly associated with distant metastasis by immunohistochemistry. VAV3 overexpression was an independent poor survival indicator (hazard ratio=15.27, P<0.05) by multivariate Cox analysis. The further functional assay revealed that VAV3 knockdown regulated CSC activation and ovarian cancer cell proliferation and sensitized paclitaxel (PTX)-resistant cancer cells to PTX treatment. Taken together, we identified by high-throughput analysis of CSCs that VAV3 overexpression is a novel biomarker for poor prognosis and survival in ovarian carcinoma.

miR-145, targeting high-mobility group A2, is a powerful predictor of patient outcome in ovarian carcinoma.

MicroRNA-145 (miR-145) expression is downregulated in several human cancers, but its clinical and functional relevance to ovarian carcinoma has not yet been elucidated. This study addressed the hypothesis that miR-145 serves as a prognostic biomarker and a tumor suppressor that regulates the expression of high-mobility group A2 (HMGA2) oncoprotein in ovarian cancer. Here, we found that low miR-145 expression and HMGA2 overexpression determined by qRT-PCR and immunohistochemistry significantly correlated with advanced stage, lymph node involvement, and distant metastasis in 74 ovarian carcinomas. Low miR-145 expression significantly correlated with tumor recurrence and worse overall survival (HR=8.62, P = 0.039). Transfection of pre-miR-145 resulted in reduced cell growth and migration, and increased apoptosis of ovarian cancer cells by TUNEL, colony forming, and cell migration assays. MiR-145 was found to directly target HMGA2 by luciferase assay and Western blotting. Our findings suggest that miR-145 functions as a tumor suppressor in ovarian cancer and directly targets HMGA2 oncoprotein. Low miR-145 and high HMGA2 expressions are potential biomarkers of poor prognosis of ovarian carcinoma and miR-145 is the more powerful predictor of patient outcome.

Human papillomavirus type-16 positive endobronchial metastasis from uterine cervical cancer.

Although the lung is the most common site of metastasis from extrapulmonary malignancies, endobronchial metastases (EBM) are relatively rare. EBM typically originate from breast, colorectal, or kidney cancer. EBM from uterine cervical cancer is relatively rare and is difficult to confirm. In this study, we report a case of EBM in a patient with previously treated uterine cervical cancer. In this case, differentiation of the EBM from primary bronchogenic carcinoma with clinical, radiological, and pathologic findings was difficult. As identical human papillomavirus (HPV)-16 DNA was detected in both the EBM and in previously resected tissues from the prior uterine cervical cancer, the patient was diagnosed with EBM from uterine cervical cancer. HPV genotyping may aid in discriminating EBM from primary bronchogenic carcinoma in patients with uterine cervical cancer.